Document e5vp9bMD02YxmvMoV3Y5Vw6aq

ARox-oisy Attachments to Letter to C. Auer dated May 4, 2000 Perfluoroctane Sulfonate Studies Pharmacokinetic Studies 1) Skin Absorption Studies on Surfactants (1983) a) Report from W. C. McCormick to D. R. Ricker, dated September 26, 1983 summarizing data b) 28 Day Percutaneous Absorption Study in Rabbits with FC-95, Safety Evaluation Laboratory, Riker Laboratories, Inc., Experiment No. 0979AB0632 (FC-95) c) 28 Day Percutaneous Absorption Study in Rabbits with FC-99, Safety Evaluation Laboratory, Riker Laboratories, Inc., Experiment No. 0979AB0633, 3M Reference No. T-3988.1 (FC-99, diethanolamine salt of perfluorooctanesulfonate, assumed to be 25 % in water) 2) Single-Dose Intravenous Pharmacokinetic Study of T-6053 in Rabbits, 3M Environmental Laboratory (FC-99, diethanolamine salt of perfluorooctanesulfonate in water Lot 130, Unit 177. 0.04 % FC solids in water), November 16, 1995. Final Report - Analytical Study, which includes copy of in vivo Study No. AMDT010495.1, Hazleton Wisconsin, Inc., Project No. HWI 6329-136, 3M Reference No. T-6053.1 3) Single-Dose Dermal Absorption / Toxicity Study of T-6053 in Rabbits, 3M Environmental Laboratory, Study No. AMDT-022195.1 (FC-99, diethanolamine salt of perfluorooctanesulfonate in water Lot 130, Unit 177. 0.04 % FC solids in water), November 22, 1995. Final Report - Analytical Study, includes in vivo Study Hazleton Wisconsin, Inc., Project No. HWI 6329-137, 3M Reference No. T6053.2 4) Fluorochemical (FC) Levels in Naive Rats, 3M Medical Department, Toxciology Services, Study No. T-6316.9, DT21, Draft Report for Objective 3, May 14, 1999. 5) Analytical Data submitted to Dr. Jennifer Seed, USEPA, by letter dated May 3, 2000, including serum measurements from two in-life studies: a) Analytical data from Advanced Bioanalytical Services Study No. FACT-TOX111, with respect to Oral (Gavage) Pharmacokinetic Recovery Study of Perfluorooctane Sulfonate in Rats, Argus Laboratories Protocol No. 418-015, 3M Reference T-6295.14. 003726 Attachments to Letter to C. Auer dated May 4, 2000 Perfluoroctane Sulfonate Studies b) Analytical data from Advanced Bioanalytical Services Study No. FACT-TOX110., with respect to Oral (Gavage) Pharmacokinetic Study of Perfluorooctane Sulfonate in Rats, Argus Laboratories Protocol No. 418-013, 3M Reference T6295.12. 6) In Vitro Comparative Metabolism Study in Rat and Human Hepatocytes with Various Fluorochemicals, 3M Reference T-6295.1, study of T-6292 (N-ethyl FOSE), T-6293 (N-ethyl FOSE monophosphate ester), T-6294 (N-ethyl perfluorooctane sulfonamide), and T-6295 (Perfluorooctane Sulfonate) a) Range-finding Cytotocity Assay, SRI International Toxicology Laboratory, Study No. B010-95 - protocol and faxed results dated Oct. 26, 1995, Dec. 12, 1995, and Jan. 16, 1996 b) Metabolism of T-6292, T-6293 , T-6294, T-6295 by Rat and Human Hepatocytes, SRI International Toxicology Laboratory, Study No. B011-95 c) Advanced Bioanalytical Services, Inc., Analytical Report, Additional Characterization of Metabolites of T-6292, T-6293 and T-6294 from Rat and Human Hepatocytes by TurboIonSpray LC/MS and LC/MS/MS. SemiQuantitative Analysis of T-6295 in Rat and Human Hepatocytes Incubated with T-6292, T-6293 and T-6294 by LC/MS/MS, January 28, 1998, Report 98AGKP01.3M d) Working Interpretation of Results, chart entitled Perfluorosulfonamide Metabolism in Rat vs. Human Hepatocytes, updated Feb. 5, 1998 based on ABS Jan. 1998 report C02727 Internal Correspondence rc: F. D. G r iffit h - 220-2E-02 F. A. bel, M.D. - 220-2E-02 P- i To: D. R. RICKER - COMMERCIAL CHEMICALS DIVISION - 236-2B-01 From: W. C. MC CORMICK - MEDICAL, TOXICOLOGY SERVICES - 220-2E-02 Subject: Skin Absorption Studies on Surfactants Date: September 26, 1983 Attached are the fin a l reports from Riker Safety Evaluation Laboratoiy on the dermal to x ic ity and absorption studies conducted on FC-95, FC-98, FC-99, FC-128, FC-129, FC-13^ and FC-135. Each study was conducted in the following manner. Following a range finder study from which doses were selected, ten male and ten female rabbits were clipped free of hair and the te st a r tic le was place on b0% of the to ta l body surface area. An impervious p la stic sheet occluded the skin for 2b hours a fte r which time the te s t a r tic le was removed. Animals were maintained and observed for a 28 day period. Blood samples were obtained on days 1, 7, 1^ and 28. Analysis of day 1 and 28 fluorine levels were made for a single male and female for each compound. I n i t i a l , 7, 1^ and 28 day body weights were recorded. Surviving animals were sacrificed and necropsied on day 28. FC-95: Two doses were used in the rangefinder study: 5,000 mg/kg and 1,000 mg/kg. No deaths or pharmacotoxic signs were observed at either dose. The higher dose level was chosen for the f u l l study. FC-95 was applied as a suspension in water at 5,000 mg/kg. Hyperactivity was noted in 5/10 males only at day 6. A ll animals recovered by day 7 and remained asymptomatic throughout the study period. Weight gains were observed for a l l rabbits. No v is ib le lesions were noted at necropsy. Analysis of day 1 and day 28 blood fluorine (to ta l) lev els showed: Total F, ppm Day 1 Day 28 Male Female 10.3 0 .9 130.2 128.0 FC-95 appears to be absorbed through the skin but is not to xic at high dermal doses. FC-95 can be considered p r a c tic a lly non-toxic dermally. 003728 FC-98: Two doses, 5,000 and 1,000 mg/kg were used in the rangefinder study. The compound was dosed as a suspension in water. No pharmacotoxic signs were noted. In the f u ll study the 5,000 mg/kg dose was used. No pharmacotoxic signs were observed. One female died as a results of a technician handling error. At necropsy, no gross lesions were noted. Blood fluorine levels were: Total F , ppm Day 1 Day 28 Male Female 271-9 226. h 9^.3 93.1 FC-98 appears to he absorbed and eliminated to some extent. The acute dermal LD50 is greater than 5 g/kg. FC-98 can be considered p ractically non-toxic dermally. FC-99: Three doses were used in a rangefinder study for FC-99, 5000-, 2000- and 1000 mg/kg. No adverse signs were seen at any dose le v e l. The 5,000 mg/kg dose was used in the f u l l study. FC-99 is a liqu id and was applied undiluted to the skin. No sig n ifica n t reactions or pharmacotoxic signs were noted. There were no deaths. Weight gains were normal. At necropsy no observable lesions were noted. Total blood fluorine levels were: Total F , ppm Day 1 Day 28 Male Female 129.1 73.5 1+2.5 111.5 FC-99 appeared to have been s lig h tly absorbed without apparent toxic e ffe c ts . The acute dermal LD50 is greater than 5 g/kg. FC-99 is considered p ra c tica lly non-toxic dermally. FC-128: Three dose levels were used on the rangefinder, 5,000-, 2, 000- and 1,000 mg/kg with 0/h-, 1 /1+, and 0/1* deaths respectively. Because of the death at 2,000 mg/kg i t was chosen as the dose level for the f u l l study. The material was applied as a suspension in water. No pharmacotoxic signs were observed. There were no deaths. Weight gains were noted in a l l males but 3/10 females lo st weight over the study period. No v isib le lesions were noted at necropsy. Blood fluorine levels were: 03729 T o t a l F , ppm Day 1 Day 28 Males Females 1.6 10.5 16.5 FC-128 appears to be re la tiv e ly poorly absorbed and is non-toxic at 2,000 mg/kg. The acute dermal LD^q is greater than 2 g/kg. FC-129: Three dose levels were used in the rangefinder, 5, 000- , 2,000- and 1,000 mg/kg. The 5,000 mg/kg dose was used in the f u l l study. The material was. applied undiluted. The dose e lic ite d a variety of pharmacotoxic signs: lethargy, prostration and hypoactivity. Five female rabbits died within 3 days of dosing. One male died a fte r 2 days. Necropsies of those dying acutely revealed pale mottled liv e rs and blood in the urine in the bladder. In general, survivors showed no lesions at necropsy (one rabbit had an atrophic spleen). Blood Fluorine levels were: Total F , ppm Day 1 Day 28 Male Female 11.U 26.1 23.3 69.6 Given the obvious to xic response of those animals to FC-129 the blood fluorine levels are not p a rticu la rly revealing. The acute dermal LD50 (female rabbits) is 5 g/kg. For males i t is greater than 5 g/kg. FC-129 can be considered s lig h tly toxic dermally. FC-13k: Three doses were used in the rangefinder: 5,000-, 2,000- and 1,000 mg/kg. The material was applied as a suspension in water. There were no deaths or pharmacotoxic signs at any dose. The f u ll study used the 5,000 mg/kg ap plication. As with the rangefinder no pharmacotoxic signs were observed. One death occurred as a result of a technician handling error. Weight gains were noted for a l l animals. No v isib le lesions were noted at necropsy. Blood fluorine le v e ls: Total F, ppm Day 1 Day 28 Males Females 18.8 0.2 23.9 I 8. I FC-13^ seems poorly absorbed through the skin. The acute dermal LD50 is greater than 5 g/kg. FC-131 can be considered non-toxic 003730 dermally. FC-135: Three dose levels were used in the rangefinder, 5,000-, 2,000- and 1,000 mg/kg. The material was applied undiluted to the skin. No pharmacotoxic signs were observed at any dose. 5,000 mg/kg was used in the f u l l study. No pharmacotoxic signs or deaths were seen. Weight gains were noted for a l l females and 8/10 males. Two males lo st weight during the f ir s t week a fte r dosing and fa ile d to gain back to th eir i n i t i a l weight. At necropsy no v is ib le lesions were observed. Blood fluorine levels were: Total F , ppm Day 1 Day 28 Male Female 2.3 1*6 6.9 20.8 FC-135 seems re la tiv e ly poorly absorbed dermally. The acute dermal LD50 is greater than 5 g/kg. FC-135 can be considered p ractically non-toxic dermally. 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